Review
Cardiovascular risk associated with sodium-containing medicines
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by Universitat de Girona on 10/17/14 For personal use only.
Li Wei†, Isla S Mackenzie, Thomas M MacDonald & Jacob George †
University College London, School of Pharmacy, Department of Practice and Policy, London, UK
1.
Introduction
2.
Physiology of sodium in the human body
3.
Source of sodium intake
4.
Association between sodium intake and blood pressure and cardiovascular disease
5.
Sodium-containing medicines
6.
Conclusion
7.
Expert opinion
Introduction: It is widely recognized that excess sodium intake increases the risk of hypertension, and this subsequently increases the risk of cardiovascular disease. Although efforts are being made to reduce sodium intake in the population in general, there are concerns that a considerable sodium load can be ingested via certain effervescent, dispersible, and soluble formulations of medicines. Areas covered: Reducing dietary sodium intake in the general population has resulted in a significant reduction in cardiovascular disease outcomes. However, no previous studies have highlighted the potential risk of cardiovascular disease by taking sodium-containing medicines such as soluble forms of aspirin, paracetamol, ibuprofen, and other common drugs. We recently conducted a nested case-control study in the UK general population using the UK Clinical Practice Research Datalink to study the long-term use of sodiumcontaining medicines and cardiovascular outcomes. The results showed that compared with standard formulations, patients who took sodium-containing medicines were 16% more likely to develop cardiovascular events (OR = 1.16, 95% CI 1.12 -- 1.21). The risks for stroke and hypertension were even higher, (1.22 [1.16 -- 1.29] and 7.18 [6.74 -- 7.65]), respectively. Expert opinion: Sodium-containing formulations should be prescribed with caution only if the perceived benefits outweigh the risks. Keywords: cardiovascular risk, observational study, public health, sodium-containing medicines Expert Opin. Drug Saf. [Early Online]
1.
Introduction
Sodium is an essential mineral element in the human body. Its main functions include maintaining water and acid balances and adjusting for blood volume. Salt from the diet is the major source of sodium and the current salt intake in many countries is between 9 and 12 g/day [1]. Both high and low sodium consumption is linked with high blood pressure, cardiovascular diseases and other adverse health outcomes such as osteoporosis, gastric cancer, and kidney disease [2-14]. However, sodium enhances the positive sensory attributes of foods and as a society we consume excess salt every day. It is not only a problem in ‘developed’ countries but also in poorer countries that have acquired a taste for high-salt, high-fat foods. Excess dietary sodium is a major and modern public health problem worldwide and poses a big challenge for governments and health care professionals around the world. Salt consumption has increased in developed nations due to large increases in the consumption of highly salted processed foods. Governmental efforts to reduce consumption have met with mixed success [15-18]. National guidelines and government initiatives on sodium intake in the last decade have played major roles in reducing daily sodium intake [19]. For example, in the UK, the mean estimated sodium intake, derived from urinary sodium excretion, for adults aged 19 -- 64 years was 3.2 g/day in 2011. Men had a mean estimated intake of 3.7 g/day, and women had a mean estimated intake of 2.7 g/day [20]. However, 70% of participants had a daily intake of sodium higher than the recommendation 10.1517/14740338.2014.970163 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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L. Wei et al.
Article highlights. .
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Some common sodium-containing medicines such as soluble paracetamol contain 3.4 g of sodium at maximum daily dose. This is well above the recommended total daily sodium intake of 2.4 g for an adult. Patients who regularly take sodium-containing formulations of aspirin, paracetamol, and ibuprofen and other medications are 16% more at risk of cardiovascular events, 22% more prone to stroke, and seven times more likely to develop hypertension compared with patients taking non-sodium-containing formulations of the same drugs. People should be warned about the potential dangers of high sodium intake from medications and sodiumcontaining formulations should be prescribed with caution only if the perceived benefits outweigh the risks. Clearer labeling on medicines is needed to reduce the risk of cardiovascular events potentially due to taking tablets with high sodium content. The pharmaceutical industry should strive to produce soluble medicines that do not contain sodium wherever possible.
This box summarizes key points contained in the article.
of no more than 2.4 g/day, which was set up two decades ago in the UK by the Committee on Medical Aspects of Food and Nutrition Policy (COMA) [21] and is now widely accepted by many countries in the world. The United Kingdom’s National Institute for Health and Care Excellence (NICE) published its public health guidance: Prevention of Cardiovascular Disease in 2010 aiming to reduce adult sodium intake to 2.4 g/day by 2015 and 1.2 g/day by 2025, with lower target levels for children [22]. Adults should consume < 2 g of sodium, or 5 g of salt, and at least 3.5 g of potassium per day, according to new guidelines issued by the WHO last year [23]. 2.
Physiology of sodium in the human body
Sodium is the key chemical responsible for exerting an osmotic effect in all compartments of the body and crucially, within the intravascular space. It is essential in maintaining extracellular fluid (ECF) balance and, thus, volume status. It is a vital constituent of the body and thus is an essential nutrient. Most human physiological and biological processes function correctly only when sufficient quantities of sodium are present. The main function of sodium is to maintain blood volume and blood pressure. In general, sodium retention results in water retention and sodium loss results in water loss [24,25]. The mechanism maintaining the balance between blood pressure and sodium excretion is known as pressure natriuresis. Blood pressure regulation is linked to the kidney’s ability to excrete or conserve enough sodium to maintain the body’s normal sodium content, ECF volume, and blood volume, in response to variations in sodium intake and losses [26]. 2
Other functions include maintenance of membrane potentials -- sodium and chloride are electrolytes that respond to the maintenance of concentration and charge differences across cell membranes, and nutrient absorption and transport -- the absorption of chloride, amino acids, glucose, and water transported by sodium through nutrient gateways. It is also essential for the maintenance of muscle and nerve activity. Sodium loading of healthy individuals impairs endothelial function, left ventricular relaxation, and cardiac repolarization [27]. Some of these effects may be independent of blood pressure in hypertensive patients [28]. Excess sodium intake has BP-independent effects, promoting left ventricular hypertrophy as well as fibrosis in the heart, kidneys, and arteries [29]. In contrast, adverse effects on some physiological parameters such as activation of the renin and aldosterone system and increased catecholamines occur when patients have low sodium intake level (i.e., < 2.0 g/day) [30,31]. Urinary sodium excretion is a biomarker that provides a direct measurement of sodium intake. A 24-h urine collection is considered the ‘gold standard’ to capture usual sodium intake, because in a steady state of normal individuals, nearly 100% of dietary sodium is excreted in urine [32]. People are either salt-sensitive or salt-resistant measured by how blood pressure responds to salt intake. Those who are sensitive to salt are more likely to have high blood pressure than those who are resistant. Salt-sensitive subjects tend to have a higher body mass index than salt-resistant subjects. Some consistent demographic factors, such as older age, black race, and perhaps female sex, have been shown to be associated with an increased frequency of salt sensitivity. Additionally, salt-sensitive subjects are reported to have lower levels of renin and aldosterone than their salt-resistant counterparts [33]. 3.
Source of sodium intake
Salt, which is composed of 40% sodium and 60% chloride, is the primary source of sodium in our diet. Sodium has been found in a number of compounds used in food manufacturing and preparation, as well as in medicines and some water supplies [34]. Foods such as pizza, sandwiches and soups, protein foods, and grains contribute two-thirds of sodium intake [35]. In Europe, about three-quarters of sodium intake comes from commercially processed food [1,36]. Naturally occurring sodium in unprocessed foods contributes ~15% of total sodium intake [21]. More than 75% of the sodium Americans eat comes from restaurants, pre-packaged, and processed foods. Only 5% of dietary sodium is added during home cooking and only 6% is added at the table [37,38]. The current guidelines about sodium intake from developed countries focus on food sodium intake and reducing sodium intake in general population has been considered one of the most cost-effective measures to improve public health [39,40]. Reducing population sodium consumption is a top priority in many nations in the prevention of cardiovascular disease
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Cardiovascular risk associated with sodium-containing medicines
with strong commitment from government, industry, health professional, and public volunteers [41]. However, we are a long way from achieving the goal of maximum salt intake of 6 g/day globally. Although food products have been labeled ingredients, multinational food companies have different amounts of salt added to the same branded products in different countries [42]. Compared with food products, sodium intake from other sources such as commonly prescribed medicines has been largely ignored.
Association between sodium intake and blood pressure and cardiovascular disease
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4.
The NICE published an evidence update for prevention of cardiovascular disease in January 2014 [43]. It provides the most up-to-date evidence in relation to prevention of cardiovascular disease. The relationship between sodium intake and cardiovascular risk in humans was first time recognized 60 years ago [44]. The strength of this relationship has been demonstrated in large studies such as the INTERSALT study involving more than 10,000 patients; populations with a high sodium intake had a stronger relationship between blood pressure and age compared to populations with a low sodium intake [3]. Evidence from randomized clinical trials There have been many randomized trials that have investigated the effects of sodium reduction on blood pressure in adults [45,46]. The most persuasive evidence on the effects of sodium on blood pressure comes from rigorously controlled, dose-response trials such as a study published in The Lancet in 1989 [47] and a study published in New England Journal of Medicine in 2001 [48]. The Dietary Approaches to Stop Hypertension Sodium trial reported a significant dose--response relationship between sodium intake and blood pressure [49]. Reduction in sodium intake by half (from 4 to 2 g/day) in older people successfully reduced blood pressure (7.2/3.2 mmHg in hypertensive patients and 8.3/2.9 mm Hg in normotensive patients) [50]. A meta-analysis [12] of these trials documented that a 100 mmol reduction in 24 h urinary sodium (6 g/day salt) was associated with a fall in systolic blood pressure of 5.8 mmHg (95%CI: 2.5 to 9.2, p = 0.001) after adjusting for age, ethnic group, and blood pressure status [51]. It concluded that a modest reduction in salt intake for four or more weeks causes significant and, from a population viewpoint, an important fall in blood pressure in both hypertensive and normotensive individuals, irrespective of sex and ethnic group. The observed significant association between the reduction in 24-h urinary sodium and the fall in systolic blood pressure indicates that larger reductions in sodium intake will lead to larger falls in systolic blood pressure [51]. These results support the population sodium reduction strategies, which will reduce sodium impact on blood pressure and cardiovascular disease. 4.1
The current recommendations to reduce salt intake from 9 -- 12 to 5 -- 6 g/day (i.e., 3.6 -- 4.8 to 2 -- 2.4 g/day for sodium intake) will have a major effect on blood pressure, but a further reduction to 3 g/day for salt intake (i.e., 1.2 g/ day for sodium intake) will have a greater effect and should become the long-term target for population salt intake [51]. A randomized cross-over study also showed that a reduction of 1.2 g/day from a usual 3.6 g/day sodium diet improves endothelial function and decreases endothelin-1 in normotensive overweight and obese subjects [32]. Dietary sodium restriction is also linked with significant short-term improvements of blood pressure (mean reduction of systolic/diastolic blood pressure, 10/4 mmHg; 95% confidence interval, 5 -- 15/1 -- 6 mmHg), ECF volume, albuminuria, and proteinuria in patients with moderate-to-severe chronic kidney disease suggesting that patients with chronic kidney disease are particularly salt sensitive [52]. A modest reduction in sodium intake is linked with significant reduction of blood pressure in children and adolescents [53]. Evidence from observational studies In 1988, The International Study of Salt and Blood Pressure (INTERSALT study), involving > 10,000 patients from 52 centers around the world found that sodium was significantly related to the slope of blood pressure with age [4]. Since then many studies have been carried out to study the relationship between sodium intake and blood pressure, cardiovascular outcome and mortality and a number of meta-analyses have been carried out to summarize the overall results. In a recent meta-analysis of observational studies, a higher sodium intake was associated with an increased risk of stroke (pooled relative risk 1.23, 95% confidence interval 1.06 -- 1.43; p = 0.007) and cardiovascular disease (1.14, 0.99 -- 1.32; p = 0.07) [2]. Graudal et al. published a meta-analysis of observational studies in April 2014 about sodium intake and mortality outcome [14]. They studied 23 cohort studies and found that compared with usual sodium intake (mean daily sodium intake of 115 -- 215 mmol), both low sodium intakes (mean daily sodium intake < 115 mmol) and high sodium intakes (mean daily sodium intake > 165 mmol) are associated with increased mortality. A recent cross-sectional study [16] was conducted in the UK to evaluate the impact of a national strategy to reduce population levels of salt intake, introduced in 2003. The study found that there were significant reductions in salt intake between 2003 and 2007 (-0.175 g per day per year). An up-to-date study [54] published in 2014 showed that from 2003 to 2011, sodium intake felt from 3.8 g/day in 2003 to 3.2 g/day in 2011 and during the same period there was a decrease in mortality from stroke by 42% (p < 0.001) and ischemic heart disease by 40% (p < 0.001). The authors conclude that reduction in sodium intake is likely to be an important contributor to the falls in blood pressure from 2003 to 2011 in England. However, reduction of other risk factors of cardiovascular disease such as smoking may also contribute to the reduction of 4.2
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cardiovascular mortality. In addition, higher sodium intake is also associated with increased total mortality in the general United States (US) population [55]. Bibbins-Domingo et al. conducted a modeling study [40] assessing the potential effect of population-wide reductions in dietary sodium intake on population health and compared it with other public health and clinical interventions. Potential impacts of sodium reduction were examined using the Coronary Heart Disease Policy Model -- a computer simulation of heart disease in adults aged 35 -- 84 years, with an extension of the model to assess stroke. It was estimated that a 1.2 g/day reduction in sodium intake could lead to annual reductions in the number of new cases of: coronary heart disease by 60,000 -- 120,000, stroke by 32,000 -- 66,000, and myocardial infarction by 54,000 -- 99,000. The annual number of deaths from any cause could also be reduced by 44,000 -- 92,000 [40]. Economic impact NICE public health guidance 25 states that changes in cardiovascular disease risk factors brought about by intervening at the population level could lead to substantial benefits [22]. Several cost-effectiveness analyses have shown that sodium intake reduction is likely to be very cost-effective [16]. Barton et al. developed an economic model to estimate the cost effectiveness of a population-wide risk factor reduction program aimed at preventing cardiovascular disease in England and Wales [56]. A program reducing cardiovascular events by 1% could result in a gain of 98,000 quality-adjusted life years (QALYs) and NHS savings of at least £30 million a year compared with no intervention. Reducing dietary sodium intake by 1.2 g/day could see a gain of 131,000 QALYs, with savings of £40 million a year. In response to a 2010 report by the Institute of Medicine, [34], The National Salt Reduction Initiative set out a strategy in 2010 to reduce population sodium consumption in the US by 20% in 5 years. Reducing sodium intake in the US to the recommended 2.3 g/day would prevent 11 million cases of hypertension, save $18 billion health care dollars, and gain 312,000 QALYs valued at $32 billion annually [57]. A regulatory intervention designed to achieve a reduction in sodium intake of 1.2 g per day would save 194,000 -- 392,000 QALYs and $10 billion -- $24 billion in health care costs annually [40]. 4.3
5.
Sodium-containing medicines
Many commonly prescribed medicines contain significant amounts of sodium, including effervescent and soluble analgesics in order to improve their absorption into the body. For example, the soluble and effervescent formulations of paracetamol 500 mg contain 0.43 and 0.41 g of sodium in each tablet, respectively. The common daily dose (also the maximum daily dose) for paracetamol is eight tablets per day, which will result in a total of 3.42 and 3.11 g of sodium intake through ingestion. This is well above the 4
recommended total daily allowance of 2.4 g/day for sodium intake for an adult in the UK without considering any food intake. Soluble ibuprofen (200 mg), a commonly used NSAID, can contain 1.2 g sodium if the maximum daily dose is taken. Over the last two decades, large public health efforts have been made to tackle the problem of high sodium intake through food in the population. However, there has been much less research attention on the impact of large amounts of sodium intake by medicines on health. A few studies with small sample size have reported a reduced blood pressure in patients who switched from effervescent preparations of paracetamol to non-effervescent preparations in the last 10 years [58,59]. About a quarter of million patients each year have soluble paracetamol prescriptions in the UK and many paracetamol tablets are sold over-the-counter as well. However, patients are not aware of the large amount of sodium contained in each tablet. Unlike foods, pharmaceutical companies are not subject to any legally binding restrictions with regard to sodium content or labeling of these sodiumcontaining medicines. We have recently conducted a large nested case-control study (61,072 cases vs 61,072 controls) in the UK general population using the UK Clinical Practice Research Datalink to study the long-term use of sodium-containing medicines and its cardiovascular outcome [60]. The study identified the most commonly prescribed sodium-containing medicines including dispersible, effervescent, and soluble medicines (24 medicines) and its comparable standard formulations (116 medicines), which were non-dispersible, non-effervescent, or non-soluble versions of the 24 sodium-containing medications. Examples of sodium-containing formulations are shown in Table 1. The vast majority of patients who are prescribed simple analgesics are advised this at maximum dose as per the WHO analgesic ladder to avoid subtherapeutic pain relief. The study consisted of 1.29 million adult patients defined as age ‡18 years old. The average follow-up time of the study was 7.23 years. The study outcome was any cardiovascular event during the follow-up period, defined by the Antithrombotic Trialists’ Collaboration serious vascular event composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or vascular death [61]. The median sodium consumption from sodium-containing medications alone in the study was 2.5 g/day -- this amount exceeds the current recommended sodium daily intake of 2.4 g/day. Compared with standard formulations, patients who had sodium-containing medicines were 16% more likely to develop cardiovascular events (OR = 1.16, 95% CI 1.12 -- 1.21). The ORs for the secondary endpoints of stroke, all-cause mortality, and hypertension were 1.22 (1.16 -- 1.29), 1.28 (1.23 -- 1.33), and 7.18 (6.74 -- 7.65), respectively. The increased risk of stroke in the sodium-containing medicines group compared with standard medicines group is supported by large published studies including a recent meta-analysis [62]. A 28% increased risk of mortality was comparable with
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Cardiovascular risk associated with sodium-containing medicines
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Table 1. Sodium content information for selected sodium-containing formulations. Formulation
Na+ per tablet (g)
Common daily Na+ (g/day)
Paracetamol soluble tablet 500 mg Paracetamol with codeine phosphate effervescent tablet 500 mg + 30 mg Co-codamol sugar-free effervescent powder 30 mg + 500 mg Paracetamol with codeine phosphate effervescent tablet 500 mg + 8 mg Paracetamol with codeine phosphate effervescent tablet 500 mg + 30 mgPreparation 1 Paracetamol with codeine phosphate effervescent tablet 500 mg + 30 mgPreparation 2 Paracetamol soluble tablet 120 mg Metoclopramide with aspirin effervescent tablet 5 mg + 325 mg Metoclopramide with aspirin effervescent tablet 5 mg + 450 mg Ibuprofen soluble tablet 200 mg Ascorbic acid effervescent tablet 1 g Aspirin effervescent tablet 300 mg Zinc sulfate sugar-free effervescent tablets 125 mg Zinc sulfate monohydrate effervescent tablet125 mg Calcium gluconate effervescent tablet 1 g Calcium lactate gluconate with calcium carbonate effervescent tablets 2263 mg + 1750 mg Calcium carbonate with colecalciferol effervescent tablet 1500 mg + 10 mcg
0.43 0.41 0.41 0.39 0.39
3.42 3.28 3.28 3.11 3.11
0.33
2.61
0.08 0.28 0.28 0.20 0.19 0.15 0.11 0.11 0.10 0.14
1.29 1.66 1.10 1.21 0.19 0.15 0.32 0.32 0.83 0.14
0.05
0.11
the finding from the Third National Health and Nutrition Examination Survey, which found a 20% increased all-cause mortality in the higher sodium intake group (HR 1.20; 95% CI 1.03 -- 1.41 per 1000 mg/day) [63]. Douglas and Akil demonstrated in a case study that an increase in blood pressure seemed to be temporally related to the switch in drug (from insoluble Panadol to soluble Panadol), which substantially increased the sodium intake in a female patient with polymyalgia rheumatica [59]. Ubeda and colleagues conducted a small observational study (n = 34) to investigate the effect of sodium-containing medicines on blood pressure in elderly uncontrolled hypertensive patients who were treated with effervescent paracetamol (3 g/day) for osteoarthritis [58]. They found that switching paracetamol from effervescent to standard formulation for 4 weeks or more was associated with a blood pressure reduction of 13.1/2.5 mmHg. These two studies together with George’s study [58-60] a biologically plausible mechanism to support a potential causal association between sodiumcontaining medicines and increased cardiovascular risk. 6.
Conclusion
Patients who are exposed to sodium-containing effervescent, dispersible, and soluble medications may have an increased risk of cardiovascular disease when compared with patients who received standard formulations of the same drugs. The results of this study suggest that “physicians should prescribe sodium-containing formulations with caution and only if there are compelling reasons to do so. Sodium-loaded effervescent, soluble, or dispersible tablets should be avoided
in patients at risk of hypertension, and patients prescribed these drugs should be carefully monitored for the emergence of hypertension” [60]. 7.
Expert opinion
Blood pressure rises linearly with sodium intake. This relationship was proposed by Lewis Dahl 60 years ago [44] and has been confirmed by many later studies [5,31,52,64]. Substantial public health efforts in the last two decades have focused on the reduction of dietary sodium intake. A wide range of health initiatives [65-71] in developed countries have shown that dietary sodium intake has reduced over the past decade [16]. However, the rise of the ageing population means that more patients will now have co-morbidities and polypharmacy -- the concurrent use of four or more medications by one individual. This provides a great risk of high daily sodium intake through medication ingestion alone and demands attention at clinical policy and practice level [72]. The presence and amount of sodium in medications and its impact on health have not been investigated until a recent study by our group [60]. Sodium-containing medicines such as soluble aspirin, paracetamol, ibuprofen, and other common drugs have been widely used as pain relief in the treatment of many chronic conditions for decades. Many old people take it regularly as part of their disease management. The maximum daily dose of eight tablets of dispersible paracetamol 500 mg results in the ingestion of 3.4 g well in excess of the recommended sodium intake of 2.4 g per day for an adult in the UK. Exposure to sodium-containing formulations of effervescent, dispersible, and soluble medicines was associated with a
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16% increased risk of cardiovascular events and sevenfold increased risk of hypertension when compared with standard formulations of those same drug [60]. Patients should be warned about the potential dangers of high sodium intake from prescribed and over-the-counter medicines. The medicines should be used if the perceived benefits outweigh the risks and patients should be monitored for the emergence of hypertension. For those patients who are at risk of cardiovascular events and who are on a low-salt diet such as heart failure, sodium-containing medicines should be avoided as far as practicably possible. The study of sodium-containing medicines and its cardiovascular risk [60] has some limitations as it stated in the original publication. In summary, the study was not able to control for dietary sodium intake and over-the-counter medicines and vitamin supplements in effervescent, dispersible, and soluble formulations [73]. To give us an idea of where these risks translate for medicines bought over the counter, we would need to see further research focusing on nonprescription medicine. There might be coding errors for the exposures, outcomes, and covariates in the database as this is a common limitation for database research. Data on unmeasured risk factors such as health behavior including poor diet and less contacts with health professionals, and family history were not available. Therefore, confounding and bias could not be fully adjusted in the study. It might be that taking sodium-containing medicines is associated with less good health behavior and that this led to fewer contacts with health professionals [60]. This aspect requires further exploration. The study also assumed that if a prescription was prescribed then patients would adhere to treatment but we had no way of knowing whether patients actually took the pills. However, this problem is not unique and in fact applies to the vast majority of studies including randomized controlled trials [74]. “On the basis that people who take sodium-containing formulations do so for a reason it is likely that consumption of over-the-counter drugs would mirror prescribed formulations and this could tend to amplify the total sodium load” [60].
6
The sodium-containing medicines appear to be an important topic that needs to be addressed by regulatory agencies. We believe that the findings of association between sodiumcontaining medicines and cardiovascular risk are of profound public health importance. A discussion between regulatory authorities, government, and industry regarding sodium content in medicine would be welcomed. “As a minimum, the public should be warned about the potential hazards of high sodium consumption in prescribed medicines and these should be clearly labeled with the sodium content in the same way as foods are labeled. Although we did not study over-the-counter medicines, we think that it is reasonable to extrapolate our findings to these medicines. Arguably, over-the-counter preparations that have more questionable therapeutic benefit might have their risk/benefit balance reassessed. Pharmaceutical innovation to reduce the sodium content of medications while preserving the desired effervescent, soluble, or dispersible characteristics would seem to be a wholly desirable goal” [60]. Further research on the relationship between sodiumcontaining medicines and public health from different populations is needed. Although the sodium study [60] found an association between prescribed sodium-containing medicines and risk of hypertension, stroke, and all-cause mortality, the study did not detect a statistically significant increased risk of myocardial infarction or vascular death. The study therefore limits its support to only an effect of sodium-induced hypertension, and an increased incidence of stroke [60].
Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.
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George J, Majeed W, Mackenzie IS, et al. Association between cardiovascular events and sodium-containing effervescent, dispersible, and soluble drugs: nested case-control study. BMJ 2013;347:f6954 This is the first study to show an association between sodium-containing medicines and risk of cardiovascular events.
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Affiliation
Li Wei†1 MBChB MSc MPH PhD, Isla S Mackenzie2 PhD FRCP Edin, Thomas M MacDonald3 MD FRCP & Jacob George4 MD FRCP † Author for correspondence 1 Senior Lecturer in Epidemiology and Medical Statistics, University College London, School of Pharmacy, Department of Practice and Policy, Entrance A, BMA House, Tavistock Square, London WC1H 9JP, UK Tel: +44 020 7874 1275; Fax: +44 020 7387 5693; E-mail: [email protected] 2 Clinical Senior Lecturer in Clinical Pharmacology, University of Dundee, Dundee, UK 3 Professor of Clinical Pharmacology and Pharmacoepidemiology, Farr Institute, University of Dundee, Ninewells Hospital and Medical School, Farr Institute, Medical Research Institute, Medicines Monitoring Unit, Dundee DD1 9SY, UK 4 Clinical Senior Lecturer/Hon. Consultant in Clinical Pharmacology, University of Dundee, Dundee, UK
9
Cardiovascular risk associated with sodium-containing medicines
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by Universitat de Girona on 10/17/14 For personal use only.
Li Wei†, Isla S Mackenzie, Thomas M MacDonald & Jacob George †
University College London, School of Pharmacy, Department of Practice and Policy, London, UK
1.
Introduction
2.
Physiology of sodium in the human body
3.
Source of sodium intake
4.
Association between sodium intake and blood pressure and cardiovascular disease
5.
Sodium-containing medicines
6.
Conclusion
7.
Expert opinion
Introduction: It is widely recognized that excess sodium intake increases the risk of hypertension, and this subsequently increases the risk of cardiovascular disease. Although efforts are being made to reduce sodium intake in the population in general, there are concerns that a considerable sodium load can be ingested via certain effervescent, dispersible, and soluble formulations of medicines. Areas covered: Reducing dietary sodium intake in the general population has resulted in a significant reduction in cardiovascular disease outcomes. However, no previous studies have highlighted the potential risk of cardiovascular disease by taking sodium-containing medicines such as soluble forms of aspirin, paracetamol, ibuprofen, and other common drugs. We recently conducted a nested case-control study in the UK general population using the UK Clinical Practice Research Datalink to study the long-term use of sodiumcontaining medicines and cardiovascular outcomes. The results showed that compared with standard formulations, patients who took sodium-containing medicines were 16% more likely to develop cardiovascular events (OR = 1.16, 95% CI 1.12 -- 1.21). The risks for stroke and hypertension were even higher, (1.22 [1.16 -- 1.29] and 7.18 [6.74 -- 7.65]), respectively. Expert opinion: Sodium-containing formulations should be prescribed with caution only if the perceived benefits outweigh the risks. Keywords: cardiovascular risk, observational study, public health, sodium-containing medicines Expert Opin. Drug Saf. [Early Online]
1.
Introduction
Sodium is an essential mineral element in the human body. Its main functions include maintaining water and acid balances and adjusting for blood volume. Salt from the diet is the major source of sodium and the current salt intake in many countries is between 9 and 12 g/day [1]. Both high and low sodium consumption is linked with high blood pressure, cardiovascular diseases and other adverse health outcomes such as osteoporosis, gastric cancer, and kidney disease [2-14]. However, sodium enhances the positive sensory attributes of foods and as a society we consume excess salt every day. It is not only a problem in ‘developed’ countries but also in poorer countries that have acquired a taste for high-salt, high-fat foods. Excess dietary sodium is a major and modern public health problem worldwide and poses a big challenge for governments and health care professionals around the world. Salt consumption has increased in developed nations due to large increases in the consumption of highly salted processed foods. Governmental efforts to reduce consumption have met with mixed success [15-18]. National guidelines and government initiatives on sodium intake in the last decade have played major roles in reducing daily sodium intake [19]. For example, in the UK, the mean estimated sodium intake, derived from urinary sodium excretion, for adults aged 19 -- 64 years was 3.2 g/day in 2011. Men had a mean estimated intake of 3.7 g/day, and women had a mean estimated intake of 2.7 g/day [20]. However, 70% of participants had a daily intake of sodium higher than the recommendation 10.1517/14740338.2014.970163 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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Article highlights. .
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Some common sodium-containing medicines such as soluble paracetamol contain 3.4 g of sodium at maximum daily dose. This is well above the recommended total daily sodium intake of 2.4 g for an adult. Patients who regularly take sodium-containing formulations of aspirin, paracetamol, and ibuprofen and other medications are 16% more at risk of cardiovascular events, 22% more prone to stroke, and seven times more likely to develop hypertension compared with patients taking non-sodium-containing formulations of the same drugs. People should be warned about the potential dangers of high sodium intake from medications and sodiumcontaining formulations should be prescribed with caution only if the perceived benefits outweigh the risks. Clearer labeling on medicines is needed to reduce the risk of cardiovascular events potentially due to taking tablets with high sodium content. The pharmaceutical industry should strive to produce soluble medicines that do not contain sodium wherever possible.
This box summarizes key points contained in the article.
of no more than 2.4 g/day, which was set up two decades ago in the UK by the Committee on Medical Aspects of Food and Nutrition Policy (COMA) [21] and is now widely accepted by many countries in the world. The United Kingdom’s National Institute for Health and Care Excellence (NICE) published its public health guidance: Prevention of Cardiovascular Disease in 2010 aiming to reduce adult sodium intake to 2.4 g/day by 2015 and 1.2 g/day by 2025, with lower target levels for children [22]. Adults should consume < 2 g of sodium, or 5 g of salt, and at least 3.5 g of potassium per day, according to new guidelines issued by the WHO last year [23]. 2.
Physiology of sodium in the human body
Sodium is the key chemical responsible for exerting an osmotic effect in all compartments of the body and crucially, within the intravascular space. It is essential in maintaining extracellular fluid (ECF) balance and, thus, volume status. It is a vital constituent of the body and thus is an essential nutrient. Most human physiological and biological processes function correctly only when sufficient quantities of sodium are present. The main function of sodium is to maintain blood volume and blood pressure. In general, sodium retention results in water retention and sodium loss results in water loss [24,25]. The mechanism maintaining the balance between blood pressure and sodium excretion is known as pressure natriuresis. Blood pressure regulation is linked to the kidney’s ability to excrete or conserve enough sodium to maintain the body’s normal sodium content, ECF volume, and blood volume, in response to variations in sodium intake and losses [26]. 2
Other functions include maintenance of membrane potentials -- sodium and chloride are electrolytes that respond to the maintenance of concentration and charge differences across cell membranes, and nutrient absorption and transport -- the absorption of chloride, amino acids, glucose, and water transported by sodium through nutrient gateways. It is also essential for the maintenance of muscle and nerve activity. Sodium loading of healthy individuals impairs endothelial function, left ventricular relaxation, and cardiac repolarization [27]. Some of these effects may be independent of blood pressure in hypertensive patients [28]. Excess sodium intake has BP-independent effects, promoting left ventricular hypertrophy as well as fibrosis in the heart, kidneys, and arteries [29]. In contrast, adverse effects on some physiological parameters such as activation of the renin and aldosterone system and increased catecholamines occur when patients have low sodium intake level (i.e., < 2.0 g/day) [30,31]. Urinary sodium excretion is a biomarker that provides a direct measurement of sodium intake. A 24-h urine collection is considered the ‘gold standard’ to capture usual sodium intake, because in a steady state of normal individuals, nearly 100% of dietary sodium is excreted in urine [32]. People are either salt-sensitive or salt-resistant measured by how blood pressure responds to salt intake. Those who are sensitive to salt are more likely to have high blood pressure than those who are resistant. Salt-sensitive subjects tend to have a higher body mass index than salt-resistant subjects. Some consistent demographic factors, such as older age, black race, and perhaps female sex, have been shown to be associated with an increased frequency of salt sensitivity. Additionally, salt-sensitive subjects are reported to have lower levels of renin and aldosterone than their salt-resistant counterparts [33]. 3.
Source of sodium intake
Salt, which is composed of 40% sodium and 60% chloride, is the primary source of sodium in our diet. Sodium has been found in a number of compounds used in food manufacturing and preparation, as well as in medicines and some water supplies [34]. Foods such as pizza, sandwiches and soups, protein foods, and grains contribute two-thirds of sodium intake [35]. In Europe, about three-quarters of sodium intake comes from commercially processed food [1,36]. Naturally occurring sodium in unprocessed foods contributes ~15% of total sodium intake [21]. More than 75% of the sodium Americans eat comes from restaurants, pre-packaged, and processed foods. Only 5% of dietary sodium is added during home cooking and only 6% is added at the table [37,38]. The current guidelines about sodium intake from developed countries focus on food sodium intake and reducing sodium intake in general population has been considered one of the most cost-effective measures to improve public health [39,40]. Reducing population sodium consumption is a top priority in many nations in the prevention of cardiovascular disease
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Cardiovascular risk associated with sodium-containing medicines
with strong commitment from government, industry, health professional, and public volunteers [41]. However, we are a long way from achieving the goal of maximum salt intake of 6 g/day globally. Although food products have been labeled ingredients, multinational food companies have different amounts of salt added to the same branded products in different countries [42]. Compared with food products, sodium intake from other sources such as commonly prescribed medicines has been largely ignored.
Association between sodium intake and blood pressure and cardiovascular disease
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4.
The NICE published an evidence update for prevention of cardiovascular disease in January 2014 [43]. It provides the most up-to-date evidence in relation to prevention of cardiovascular disease. The relationship between sodium intake and cardiovascular risk in humans was first time recognized 60 years ago [44]. The strength of this relationship has been demonstrated in large studies such as the INTERSALT study involving more than 10,000 patients; populations with a high sodium intake had a stronger relationship between blood pressure and age compared to populations with a low sodium intake [3]. Evidence from randomized clinical trials There have been many randomized trials that have investigated the effects of sodium reduction on blood pressure in adults [45,46]. The most persuasive evidence on the effects of sodium on blood pressure comes from rigorously controlled, dose-response trials such as a study published in The Lancet in 1989 [47] and a study published in New England Journal of Medicine in 2001 [48]. The Dietary Approaches to Stop Hypertension Sodium trial reported a significant dose--response relationship between sodium intake and blood pressure [49]. Reduction in sodium intake by half (from 4 to 2 g/day) in older people successfully reduced blood pressure (7.2/3.2 mmHg in hypertensive patients and 8.3/2.9 mm Hg in normotensive patients) [50]. A meta-analysis [12] of these trials documented that a 100 mmol reduction in 24 h urinary sodium (6 g/day salt) was associated with a fall in systolic blood pressure of 5.8 mmHg (95%CI: 2.5 to 9.2, p = 0.001) after adjusting for age, ethnic group, and blood pressure status [51]. It concluded that a modest reduction in salt intake for four or more weeks causes significant and, from a population viewpoint, an important fall in blood pressure in both hypertensive and normotensive individuals, irrespective of sex and ethnic group. The observed significant association between the reduction in 24-h urinary sodium and the fall in systolic blood pressure indicates that larger reductions in sodium intake will lead to larger falls in systolic blood pressure [51]. These results support the population sodium reduction strategies, which will reduce sodium impact on blood pressure and cardiovascular disease. 4.1
The current recommendations to reduce salt intake from 9 -- 12 to 5 -- 6 g/day (i.e., 3.6 -- 4.8 to 2 -- 2.4 g/day for sodium intake) will have a major effect on blood pressure, but a further reduction to 3 g/day for salt intake (i.e., 1.2 g/ day for sodium intake) will have a greater effect and should become the long-term target for population salt intake [51]. A randomized cross-over study also showed that a reduction of 1.2 g/day from a usual 3.6 g/day sodium diet improves endothelial function and decreases endothelin-1 in normotensive overweight and obese subjects [32]. Dietary sodium restriction is also linked with significant short-term improvements of blood pressure (mean reduction of systolic/diastolic blood pressure, 10/4 mmHg; 95% confidence interval, 5 -- 15/1 -- 6 mmHg), ECF volume, albuminuria, and proteinuria in patients with moderate-to-severe chronic kidney disease suggesting that patients with chronic kidney disease are particularly salt sensitive [52]. A modest reduction in sodium intake is linked with significant reduction of blood pressure in children and adolescents [53]. Evidence from observational studies In 1988, The International Study of Salt and Blood Pressure (INTERSALT study), involving > 10,000 patients from 52 centers around the world found that sodium was significantly related to the slope of blood pressure with age [4]. Since then many studies have been carried out to study the relationship between sodium intake and blood pressure, cardiovascular outcome and mortality and a number of meta-analyses have been carried out to summarize the overall results. In a recent meta-analysis of observational studies, a higher sodium intake was associated with an increased risk of stroke (pooled relative risk 1.23, 95% confidence interval 1.06 -- 1.43; p = 0.007) and cardiovascular disease (1.14, 0.99 -- 1.32; p = 0.07) [2]. Graudal et al. published a meta-analysis of observational studies in April 2014 about sodium intake and mortality outcome [14]. They studied 23 cohort studies and found that compared with usual sodium intake (mean daily sodium intake of 115 -- 215 mmol), both low sodium intakes (mean daily sodium intake < 115 mmol) and high sodium intakes (mean daily sodium intake > 165 mmol) are associated with increased mortality. A recent cross-sectional study [16] was conducted in the UK to evaluate the impact of a national strategy to reduce population levels of salt intake, introduced in 2003. The study found that there were significant reductions in salt intake between 2003 and 2007 (-0.175 g per day per year). An up-to-date study [54] published in 2014 showed that from 2003 to 2011, sodium intake felt from 3.8 g/day in 2003 to 3.2 g/day in 2011 and during the same period there was a decrease in mortality from stroke by 42% (p < 0.001) and ischemic heart disease by 40% (p < 0.001). The authors conclude that reduction in sodium intake is likely to be an important contributor to the falls in blood pressure from 2003 to 2011 in England. However, reduction of other risk factors of cardiovascular disease such as smoking may also contribute to the reduction of 4.2
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L. Wei et al.
cardiovascular mortality. In addition, higher sodium intake is also associated with increased total mortality in the general United States (US) population [55]. Bibbins-Domingo et al. conducted a modeling study [40] assessing the potential effect of population-wide reductions in dietary sodium intake on population health and compared it with other public health and clinical interventions. Potential impacts of sodium reduction were examined using the Coronary Heart Disease Policy Model -- a computer simulation of heart disease in adults aged 35 -- 84 years, with an extension of the model to assess stroke. It was estimated that a 1.2 g/day reduction in sodium intake could lead to annual reductions in the number of new cases of: coronary heart disease by 60,000 -- 120,000, stroke by 32,000 -- 66,000, and myocardial infarction by 54,000 -- 99,000. The annual number of deaths from any cause could also be reduced by 44,000 -- 92,000 [40]. Economic impact NICE public health guidance 25 states that changes in cardiovascular disease risk factors brought about by intervening at the population level could lead to substantial benefits [22]. Several cost-effectiveness analyses have shown that sodium intake reduction is likely to be very cost-effective [16]. Barton et al. developed an economic model to estimate the cost effectiveness of a population-wide risk factor reduction program aimed at preventing cardiovascular disease in England and Wales [56]. A program reducing cardiovascular events by 1% could result in a gain of 98,000 quality-adjusted life years (QALYs) and NHS savings of at least £30 million a year compared with no intervention. Reducing dietary sodium intake by 1.2 g/day could see a gain of 131,000 QALYs, with savings of £40 million a year. In response to a 2010 report by the Institute of Medicine, [34], The National Salt Reduction Initiative set out a strategy in 2010 to reduce population sodium consumption in the US by 20% in 5 years. Reducing sodium intake in the US to the recommended 2.3 g/day would prevent 11 million cases of hypertension, save $18 billion health care dollars, and gain 312,000 QALYs valued at $32 billion annually [57]. A regulatory intervention designed to achieve a reduction in sodium intake of 1.2 g per day would save 194,000 -- 392,000 QALYs and $10 billion -- $24 billion in health care costs annually [40]. 4.3
5.
Sodium-containing medicines
Many commonly prescribed medicines contain significant amounts of sodium, including effervescent and soluble analgesics in order to improve their absorption into the body. For example, the soluble and effervescent formulations of paracetamol 500 mg contain 0.43 and 0.41 g of sodium in each tablet, respectively. The common daily dose (also the maximum daily dose) for paracetamol is eight tablets per day, which will result in a total of 3.42 and 3.11 g of sodium intake through ingestion. This is well above the 4
recommended total daily allowance of 2.4 g/day for sodium intake for an adult in the UK without considering any food intake. Soluble ibuprofen (200 mg), a commonly used NSAID, can contain 1.2 g sodium if the maximum daily dose is taken. Over the last two decades, large public health efforts have been made to tackle the problem of high sodium intake through food in the population. However, there has been much less research attention on the impact of large amounts of sodium intake by medicines on health. A few studies with small sample size have reported a reduced blood pressure in patients who switched from effervescent preparations of paracetamol to non-effervescent preparations in the last 10 years [58,59]. About a quarter of million patients each year have soluble paracetamol prescriptions in the UK and many paracetamol tablets are sold over-the-counter as well. However, patients are not aware of the large amount of sodium contained in each tablet. Unlike foods, pharmaceutical companies are not subject to any legally binding restrictions with regard to sodium content or labeling of these sodiumcontaining medicines. We have recently conducted a large nested case-control study (61,072 cases vs 61,072 controls) in the UK general population using the UK Clinical Practice Research Datalink to study the long-term use of sodium-containing medicines and its cardiovascular outcome [60]. The study identified the most commonly prescribed sodium-containing medicines including dispersible, effervescent, and soluble medicines (24 medicines) and its comparable standard formulations (116 medicines), which were non-dispersible, non-effervescent, or non-soluble versions of the 24 sodium-containing medications. Examples of sodium-containing formulations are shown in Table 1. The vast majority of patients who are prescribed simple analgesics are advised this at maximum dose as per the WHO analgesic ladder to avoid subtherapeutic pain relief. The study consisted of 1.29 million adult patients defined as age ‡18 years old. The average follow-up time of the study was 7.23 years. The study outcome was any cardiovascular event during the follow-up period, defined by the Antithrombotic Trialists’ Collaboration serious vascular event composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or vascular death [61]. The median sodium consumption from sodium-containing medications alone in the study was 2.5 g/day -- this amount exceeds the current recommended sodium daily intake of 2.4 g/day. Compared with standard formulations, patients who had sodium-containing medicines were 16% more likely to develop cardiovascular events (OR = 1.16, 95% CI 1.12 -- 1.21). The ORs for the secondary endpoints of stroke, all-cause mortality, and hypertension were 1.22 (1.16 -- 1.29), 1.28 (1.23 -- 1.33), and 7.18 (6.74 -- 7.65), respectively. The increased risk of stroke in the sodium-containing medicines group compared with standard medicines group is supported by large published studies including a recent meta-analysis [62]. A 28% increased risk of mortality was comparable with
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Cardiovascular risk associated with sodium-containing medicines
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Table 1. Sodium content information for selected sodium-containing formulations. Formulation
Na+ per tablet (g)
Common daily Na+ (g/day)
Paracetamol soluble tablet 500 mg Paracetamol with codeine phosphate effervescent tablet 500 mg + 30 mg Co-codamol sugar-free effervescent powder 30 mg + 500 mg Paracetamol with codeine phosphate effervescent tablet 500 mg + 8 mg Paracetamol with codeine phosphate effervescent tablet 500 mg + 30 mgPreparation 1 Paracetamol with codeine phosphate effervescent tablet 500 mg + 30 mgPreparation 2 Paracetamol soluble tablet 120 mg Metoclopramide with aspirin effervescent tablet 5 mg + 325 mg Metoclopramide with aspirin effervescent tablet 5 mg + 450 mg Ibuprofen soluble tablet 200 mg Ascorbic acid effervescent tablet 1 g Aspirin effervescent tablet 300 mg Zinc sulfate sugar-free effervescent tablets 125 mg Zinc sulfate monohydrate effervescent tablet125 mg Calcium gluconate effervescent tablet 1 g Calcium lactate gluconate with calcium carbonate effervescent tablets 2263 mg + 1750 mg Calcium carbonate with colecalciferol effervescent tablet 1500 mg + 10 mcg
0.43 0.41 0.41 0.39 0.39
3.42 3.28 3.28 3.11 3.11
0.33
2.61
0.08 0.28 0.28 0.20 0.19 0.15 0.11 0.11 0.10 0.14
1.29 1.66 1.10 1.21 0.19 0.15 0.32 0.32 0.83 0.14
0.05
0.11
the finding from the Third National Health and Nutrition Examination Survey, which found a 20% increased all-cause mortality in the higher sodium intake group (HR 1.20; 95% CI 1.03 -- 1.41 per 1000 mg/day) [63]. Douglas and Akil demonstrated in a case study that an increase in blood pressure seemed to be temporally related to the switch in drug (from insoluble Panadol to soluble Panadol), which substantially increased the sodium intake in a female patient with polymyalgia rheumatica [59]. Ubeda and colleagues conducted a small observational study (n = 34) to investigate the effect of sodium-containing medicines on blood pressure in elderly uncontrolled hypertensive patients who were treated with effervescent paracetamol (3 g/day) for osteoarthritis [58]. They found that switching paracetamol from effervescent to standard formulation for 4 weeks or more was associated with a blood pressure reduction of 13.1/2.5 mmHg. These two studies together with George’s study [58-60] a biologically plausible mechanism to support a potential causal association between sodiumcontaining medicines and increased cardiovascular risk. 6.
Conclusion
Patients who are exposed to sodium-containing effervescent, dispersible, and soluble medications may have an increased risk of cardiovascular disease when compared with patients who received standard formulations of the same drugs. The results of this study suggest that “physicians should prescribe sodium-containing formulations with caution and only if there are compelling reasons to do so. Sodium-loaded effervescent, soluble, or dispersible tablets should be avoided
in patients at risk of hypertension, and patients prescribed these drugs should be carefully monitored for the emergence of hypertension” [60]. 7.
Expert opinion
Blood pressure rises linearly with sodium intake. This relationship was proposed by Lewis Dahl 60 years ago [44] and has been confirmed by many later studies [5,31,52,64]. Substantial public health efforts in the last two decades have focused on the reduction of dietary sodium intake. A wide range of health initiatives [65-71] in developed countries have shown that dietary sodium intake has reduced over the past decade [16]. However, the rise of the ageing population means that more patients will now have co-morbidities and polypharmacy -- the concurrent use of four or more medications by one individual. This provides a great risk of high daily sodium intake through medication ingestion alone and demands attention at clinical policy and practice level [72]. The presence and amount of sodium in medications and its impact on health have not been investigated until a recent study by our group [60]. Sodium-containing medicines such as soluble aspirin, paracetamol, ibuprofen, and other common drugs have been widely used as pain relief in the treatment of many chronic conditions for decades. Many old people take it regularly as part of their disease management. The maximum daily dose of eight tablets of dispersible paracetamol 500 mg results in the ingestion of 3.4 g well in excess of the recommended sodium intake of 2.4 g per day for an adult in the UK. Exposure to sodium-containing formulations of effervescent, dispersible, and soluble medicines was associated with a
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L. Wei et al.
16% increased risk of cardiovascular events and sevenfold increased risk of hypertension when compared with standard formulations of those same drug [60]. Patients should be warned about the potential dangers of high sodium intake from prescribed and over-the-counter medicines. The medicines should be used if the perceived benefits outweigh the risks and patients should be monitored for the emergence of hypertension. For those patients who are at risk of cardiovascular events and who are on a low-salt diet such as heart failure, sodium-containing medicines should be avoided as far as practicably possible. The study of sodium-containing medicines and its cardiovascular risk [60] has some limitations as it stated in the original publication. In summary, the study was not able to control for dietary sodium intake and over-the-counter medicines and vitamin supplements in effervescent, dispersible, and soluble formulations [73]. To give us an idea of where these risks translate for medicines bought over the counter, we would need to see further research focusing on nonprescription medicine. There might be coding errors for the exposures, outcomes, and covariates in the database as this is a common limitation for database research. Data on unmeasured risk factors such as health behavior including poor diet and less contacts with health professionals, and family history were not available. Therefore, confounding and bias could not be fully adjusted in the study. It might be that taking sodium-containing medicines is associated with less good health behavior and that this led to fewer contacts with health professionals [60]. This aspect requires further exploration. The study also assumed that if a prescription was prescribed then patients would adhere to treatment but we had no way of knowing whether patients actually took the pills. However, this problem is not unique and in fact applies to the vast majority of studies including randomized controlled trials [74]. “On the basis that people who take sodium-containing formulations do so for a reason it is likely that consumption of over-the-counter drugs would mirror prescribed formulations and this could tend to amplify the total sodium load” [60].
6
The sodium-containing medicines appear to be an important topic that needs to be addressed by regulatory agencies. We believe that the findings of association between sodiumcontaining medicines and cardiovascular risk are of profound public health importance. A discussion between regulatory authorities, government, and industry regarding sodium content in medicine would be welcomed. “As a minimum, the public should be warned about the potential hazards of high sodium consumption in prescribed medicines and these should be clearly labeled with the sodium content in the same way as foods are labeled. Although we did not study over-the-counter medicines, we think that it is reasonable to extrapolate our findings to these medicines. Arguably, over-the-counter preparations that have more questionable therapeutic benefit might have their risk/benefit balance reassessed. Pharmaceutical innovation to reduce the sodium content of medications while preserving the desired effervescent, soluble, or dispersible characteristics would seem to be a wholly desirable goal” [60]. Further research on the relationship between sodiumcontaining medicines and public health from different populations is needed. Although the sodium study [60] found an association between prescribed sodium-containing medicines and risk of hypertension, stroke, and all-cause mortality, the study did not detect a statistically significant increased risk of myocardial infarction or vascular death. The study therefore limits its support to only an effect of sodium-induced hypertension, and an increased incidence of stroke [60].
Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.
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Cardiovascular risk associated with sodium-containing medicines
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Affiliation
Li Wei†1 MBChB MSc MPH PhD, Isla S Mackenzie2 PhD FRCP Edin, Thomas M MacDonald3 MD FRCP & Jacob George4 MD FRCP † Author for correspondence 1 Senior Lecturer in Epidemiology and Medical Statistics, University College London, School of Pharmacy, Department of Practice and Policy, Entrance A, BMA House, Tavistock Square, London WC1H 9JP, UK Tel: +44 020 7874 1275; Fax: +44 020 7387 5693; E-mail: [email protected] 2 Clinical Senior Lecturer in Clinical Pharmacology, University of Dundee, Dundee, UK 3 Professor of Clinical Pharmacology and Pharmacoepidemiology, Farr Institute, University of Dundee, Ninewells Hospital and Medical School, Farr Institute, Medical Research Institute, Medicines Monitoring Unit, Dundee DD1 9SY, UK 4 Clinical Senior Lecturer/Hon. Consultant in Clinical Pharmacology, University of Dundee, Dundee, UK
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